Changes to Systemic Function, part 2
= Exercise Function = Bilateral T2-T4 sympathectomy reduces the systolic blood pressure without affecting diastolic blood pressure and lowers the heart rate at rest and during exercise. (Kestenholz et al. 2002) Baroreflex comes into play during exercise. Exercise increases the oxygen demand by muscles. The control center must respond by shifting to a higher level of homeostasis. Sympathetic tone is elevated. The heart rate increases, the contraction strength increases. Blood pressure goes up. Surface blood vessels constrict, while vessels in the deeper tissue dilate, diverting blood toward the large muscles and vital organs. All of this goes toward delivering more oxygen to muscles and organs. Baroreceptors detect the elevated blood pressure, and deliver this message to the control center input. If the blood pressure goes high enough, baroreflex is able to override the oxygen demand message, causing the control center to "put the breaks on" a bit, by withdrawing some sympathetic tone, and increasing parasympathetic. This serves to set an upper limit on how high the blood pressure is allowed to go. Cardiac Response to Exercise After ETS In 2002 a group of Japanese surgeons studied the cardiac effects of ETS at rest and during light exercise. Maximal exercise was not studied. Below are their charts, showing reductions in essentially every measure. center| Changes in Hemodynamic Variables with Exercise after ETS CI, cardiac index; HR, heart rate; MAP, mean arterial pressure; RPP, rate-pressure product; SI, stroke index; SVR, systemic vascular resistance. *p<0.05 vs before ETS; **p<0.01 vs before ETS. The authors measured heart rate, arterial pressure, stroke volume and vascular resistance. Cardiac index is found by multiplying rate by stroke and adjusting for body size. Stroke index is stroke volume adjusted for body size. Rate-pressure-product is found by multiplying rate by pressure. These values were taken at rest (baseline) and during light exercise, both before ETS, and one year after ETS. This chart shows the percentage of change from baseline that occurs during exercise. Clearly, ETS surgery reduces every aspect of cardiac response to exercise. Combination of Individual Changes We see that ETS surgery will significantly reduce every aspect of cardiac response to exercise. We've seen that, typically the patient is unable to raise heart rate above approx. 135 bpm (see Reisfeld). This is analogous to having a regulator on a car engine, limiting the maximum speed that it can go. Thus, "putting the breaks on" via baroreflex becomes somewhat of a moot point. Cardiac denervation has ensured that heart rate is already limited well below the limit that would be established via baroreflex anyway, so on a first approximation baroreflex response to exercise is rendered useless. A certain amount of sympathetic withdrawal is no longer possible, because high sympathetic tone is not present to be withdrawn. However, parasympathetic effects are expected to be intact, thus unnaturally dominant. We have seen that ETS surgery reduces lung volume, and reduces the efficiency of carbon dioxide transfer out of the blood. We have seen that blood vessels are less able to redistribute blood into deep tissue. We have seen that blood catecholamine levels are lowered. We have seen that the brain is not selectively cooled during exercise. Put all of this together, and the following prediction appears self-evident: We call for empirical research into the effects of thoracic sympathectomy on exercise capacity. Patients should be warned about reductions to every aspect of cardiac function, diminished lung volume, etc. = Endocrine Function = The control center regulates the blood levels of many hormones. Among these is adrenaline, released by the adrenal medulla. The adrenal medulla often operates in concert with the sympathetic nervous system, and the two together are sometimes viewed as one system, the "sympatho-adrenal axis". Thus we might instinctively guess that sympathectomy could somehow affect adrenaline levels in the blood, even without an obvious direct connection. This guess would prove to be correct, as ETS has been shown to lower adrenaline levels in the blood (see Nakamura 2002, 2005). center| Effects of ETS on Plasma Levels of Noradrenaline and Adrenaline at Baseline and at Submaximal Exercise. *p<0.05 vs before ETS; **p<0.01 vs before ETS. Noradrenaline is released by sympathetic nerve terminals, so it is not surprising that blood levels of this catecholamine are reduced. However, most adrenaline is released into the bloodstream by the adrenal medulla, which is not directly affected by ETS. However, the adrenal medulla is part of the sympatho-adrenal axis, under the control of the hypothalamus, as discussed earlier. Dr. Nakamura had reported back in 1998 that ETS increases the blood level of a peptide called "atrial natriuretic peptide". So in the 2002 exercise paper he theorizes as to how this might offer clues to the mysterious low adrenaline levels: "The sympathetic ganglion is not a simple relay station but a site modulated by short inter-neurons and a variety of neurotransmitters and receptors. Therefore, T2-T3 ETS might have modified the sympathetic regulation of adrenaline secretion from the adrenal medulla. T2-T3 ETS increases the plasma level of atrial natriuretic peptide, which has widespread sympatholytic activity. T2-T3 ETS might have influenced the amount of adrenaline secreted from the adrenal medulla via changes in humoral factors such as atrial natriuretic peptide."(Nakamura 2002) Nakamura subsequently conducted a study on atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and concluded "The plasma concentrations of ANP and BNP increased after ETS, independent of hemodynamic changes, and apparently because of the release of the inhibitory effects of the cardiac sympathetic nerves on natriuretic peptide secretion." (Nakamura 2005) In other words, normally, the SNS inhibits the production of these peptides, so ETS surgery logically would cause them to increase. In turn, the peptides normally inhibit adrenaline production, so the increase in peptides brought on by ETS would further inhibit adrenaline production. Whatever the mechanism, it is now empirically confirmed that ETS surgery lowers blood levels of adrenaline. This could certainly help explain the "lowered alertness" and "chronic fatigue" reported so prevalently in the oral histories. Lowered alertness is also directly reported in empirical literature,, as we shall see in the section on mental functioning. = Immune Function = SNS as Interface Between Brain and Immune System In 2000, a team of U.S Government scientists at the National Institutes of Health released a treatise entitled "The Sympathetic Nerve - An Integrative Interface between Two Supersystems: The Brain and the Immune System." They began by pointing out that all of the immune organs have rich sympathetic innervation. "Lymphoid organs, similar to blood vessels, receive predominantly sympathetic/noradrenergic and sympathetic/neuropeptide Y (NPY) innervation." (Elenkov et al. 2000; see also Madden et al., 1995). Elenkov points out numerous effects that NE is known to have on immune function, and spends a good deal of time trying to distinguish between effects produced by NE in the blood and NE delivered by sympathetic nerve terminals. We recall that ETS surgery will lower both. The authors find significant neural release of NE in all of the immune organs. Which immune organs are denerved in thoracic sympathectomy? Does it follow the skin pattern? What types of changes in function might we expect in the denerved region, and how might these regional changes affect the whole system? NIH scientist Esther Sternberg is one of the foremost authorities on the role of the autonomic nervous system in the immune system. She is worth quoting at length: "Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: * systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; * regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; * locally, at sites of inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1- to a TH2 type pattern. Interruptions of this loop at any level '''and through multiple mechanisms, whether genetic, or through surgical or pharmacological''' interventions, can render an inflammatory resistant host susceptible to inflammatory disease." (Sternberg, 2001 emphasis added) Sternberg presents ample theoretical justification for the notion that sympathectomy would alter immune function at all three levels - local, regional and systemic. Systemic changes could certainly arise due to the lowered blood catecholamines, and regional function would be altered according to direct denervation of any immune organs innervated via the upper thoracic sympathetic ganglia. Any local response anywhere would encounter the lowered system levels. Local responses in the denerved region would also encounter denerved immune structures, which could be expected to affect inflammation and healing, among other functions. Healing Thus, in consideration of Elenkov and Sternberg, the CS model predicts: A team of Brazilian scientists decided to test the effects of sympathectomy on skin healing. The methods were straightforward. They sympathectomized rats, gave them skin cuts, and reported: "Sympathetic denervation accelerates wound contraction but delays reepithelialization (skin healing) in rats-. -Sympathetic denervation affects cutaneous wound healing, probably by a decrease in neurogenic inflammation during the initial phase of healing and the absence of catecholamines throughout the final phase." (Souza et al. 2005) Tumor Necrosis Factor Tumor Necrosis Factor, or TNF, is a cytokine which helps to kill malignant tumors. Our Norwegian orthodontists went looking into immune metabolism in rat teeth. They infected rats with bacteria which causes sores. They did a one-sided sympathectomy, to see if they could infer the role of the sympathetic nerves here. The result was that sympathetic nerves have an inhibitory effect on IL-1alpha . . .and a stimulatory effect on TNF-alpha in the intact rat pulp. (Bletsa et al. 2004) "We showed that IL-1alpha was increased but not TNF-alpha . . .on the sympathectomized side. Both IL-1alpha and TNF-alpha were expressed in unexposed pulp. TNF-alpha was significantly decreased in the denervated incisor pulp, whereas the level of IL-1alpha remained unchanged." (Bletsa et al. 2004, emphasis added) "Accumulating evidence suggests that the sympathetic nervous system modulates inflammatory responses and bone remodeling."(Haug et al. 2003) "Tumor onset time following implantation of MNB cells was significantly increased in animals sympathectomized as either neonates or as adults." (Fink et al. 1987) = Mental and Emotional Function = Anecdotal accounts of lowered mental alertness, and loss of strong emotions abound in the oral history of ETS. For example, airline pilot and ETS patient "Britton Johnson" writes: I have throughout my life always been gifted with a creative edge. From the time I was an infant I had a free flowing stream of creative thoughts and ideas. Sometimes this is in the form of witty insight other times the ability to grasp deep thought provoking ideas on the fly. If anything I may have entered the wrong career field even though I do like the challenges of flying and wouldn-t trade it for the world. I now feel that a part of the creative me has been lost and is dead. I feel certain emptiness now where there used to be an intensity that could rarely ever be diminished. The 'killer instinct' and 'flight or flight' impulses no doubt benefited me during my competitive years as a swimmer. I miss this part of me and am sad when I have to consciously think of what I am going to say without the 'instinct' kicking in. Music (something I have always loved dearly everything from rock to classical) has also become less rewarding. I feel this is partly due to the many distractions related to side effects but also a diminished response to the excitement and "feeling" that music used to bring to me. Yes I attribute these losses all to a "simple 30 minute procedure that will reduce sweating on the face and hands with very few side effects". Britton Johnson 2003 It's not difficult to imagine ETS leading to lowered alertness. After ETS, catecholamines are low, there is a loss of sympathetic tone on the cerebral artery, and baroreflex is low. This means less blood to the brain, and less adrenaline in the blood that is there. But what about this subjective loss of strong emotions? Music less rewarding? Could it be? Roz Carroll MA, is supervisor at Chiron Centre for Body Pshychotherapy. She has given a series of lectures, one entitled "The Autonomic Nervous System: Barometer of Emotional Intensity and Internal Conflict". Carrol presents the concept of "autonomic splitting", in which misdirected autonomic signals are blamed for a variety of psychological dysfunction. She gives a nice overview of the ANS role in psychophysiology, and is masterful at integrating information from various disciplines. "I believe that the functioning . . . of the autonomic nervous system is fundamentally bound up with preserving the dynamic integrity of the self." Carroll2001 Carrol's thesis offers strong theoretical support for a crucial role of the sympathetic nervous system in human emotion. Brain Studies After Pure Autonomic Failure A team of British scientists led by Hugo Critchley is interested in the role of the autonomic nervous system in human emotion, and have been doing very interesting studies on people with pure autonomic failure (PAF). Certain diseases can eat away at the autonomic nervous system, causing the gradual loss of more and more autonomic nerve function. As we might expect, the PAF patients reported feeling unemotional. "On statements designed to probe subjective emotional experience, there was a trend for PAF patients to rate themselves as feeling less emotional than controls". (Critchley et al. 2001) Later we will discuss if, and to what extent data on PAF patients might apply to ETS patients. Normal and PAF subjects were asked to perform four different sets of tasks effortless exercise, effortful exercise, effortless arithmetic, and effortful arithmetic. The researchers took PET scans of their brains. When compared to controls, the PAF patients showed significantly less activity in the posterior cingulate and medial parietal lobe, while at the same time showed significantly greater activity in the anterior cingulate. center| PET Scans Showing Differences in Brain Activity Between (a) PAF and (b) Controls During Interaction with Effort. (a) Significantly greater anterior cingulate activity (circled, peak x, y, z coordinates, 8, 10, 36, Z= 4.48, p <0.05, corrected for volume of regions predicted by the theoretical model to support second-order representations of bodily states, that is, cingulate, thalamus, superior colliculi) in PAF subjects compared to controls, mapped onto three consecutive axial sections of a standard template image derived from one subject. Vertical (z) coordinates are shown above each slice image. (b) Significantly greater posterior cingulate/medial parietal lobe activity (circled, peak x, y, z coordinates, 56, 38, Z= 4.51, p <0.05, corrected for predicted regions) in controls relative to PAF subjects, mapped onto three consecutive axial sections of a standard template image derived from one subject. PAF patients do not have brain damage. They have damage to their autonomic nervous systems. What these PET scans show us then, is that loss of autonomic nerve function down in the effector organs somehow changes how the brain works. What is known about the function of these particular brain areas? Activity in the posterior cingulate is thought to prevent distractibility. "This function of the posterior cingulate cortex appears to entail an inhibition of parietal cortices, probably for preventing distractibility." (Small et al. 2003) Activity in the medial parietal lobe, on the left side, is associated with language receptiveness. So the PAF patients could be expected to be more distractible, and less receptive to language. The anterior cingulate is known to be associated with autonomic responses. (see Bush et al. 2000). Could the increased activity in this area observed in PAF patients be a hyperactive response to the loss of input signals from effectors? Obviously emotion-driven brain changes bring about body state changes. What Critchley and colleagues discovered is that the body state changes, in turn, feedback this information to various brain centers. Emotions are dependent upon body state changes. These scientists came right out and said so. The opening sentence in their report was: Changes in bodily states, particularly those mediated by the autonomic nervous system, are crucial to ongoing emotional experience(Critchley et al. 2001, emphasis added) The British researchers had more questions, so the next year they did another study. This time they did classic fear conditioning on PAF patients and controls, and took pictures of their brains with Magnetic Resonance Imaging (MRI). Classic fear conditioning is done by combining a painful sensation, such as an electric shock, with a neutral sensation, such as the sound of a tone. The subject becomes conditioned to fear the tone, even when the shock is not present. It has been shown from earlier rat studies that the brain organs amygdala and insula show greater electrical activity and characteristic electrical patterns after fear conditioning. (see Ledoux website). So Critchley took MRI pictures of the patients' amygdalas and insulas before and after the fear conditioning, and showed that in humans, like rats, normal subjects would show increased activity of the amygdala after fear conditioning. The PAF patients, however, failed to develop the characteristic changes observed in control subjects. Again, we see that the brain-ANS interface is very much a "two-way street". The brain informs the ANS, but the ANS informs the brain also. center| Reduced Activity in PAF Patients Relative to Controls After Classic Fear Conditioning Reduced Activity in PAF patients, relative to controls, during conditioning to unmasked stimuli. The influence of autonomic arousal on conditioning was determined by random effects comparison of regional brain activity associated with positive conditioned stimulus versus negative conditioned stimulus in controls and PAF subjects who demonstrated behavioral conditioning. Significant differential activity between the groups is shown superimposed upon a normalized structural template image. "Absent autonomic responsivity, and therefore blunting of arousal-related representations, is associated with attenuated conditioning-related activity in insula, amygdalae, and right anterior hippocampus." (Critchley, et al. 2002) Pure Autonomic Failure vs. ETS Bear in mind now that these brain studies were done on Pure Autonomic Failure patients, not ETS patients. PAF patients have a (more or less) complete loss of autonomic function, compared with the regional loss of sympathetic function in ETS. Still, recall Goldstein's neurocardiology work. Goldstein studies both PAF and ETS, and plots ETS patients just where we would expect - in the middle - more functional than PAF, but less functional than normal. It seems reasonable to think the changes in brain function documented by Critchley would follow the same pattern - that ETS would produce the same types of brain changes as seen in PAF, but to a'' lesser degree''. Perhaps Dr. Critchley would like to study ETS patients, and we call on him to do so. ETS as Psychosurgery In consideration of Critchley then, and accepting the notion that his results are applicable to the corposcindosis model, two more predictions are made. The empirical confirmation for the previous two predictions comes from Finland, where we find the Privatix psychiatric clinic. Founded by surgeon/psychiatrist Timo Telaranta, Privatix specializes in performing ETS surgery to treat psychiatric conditions such as anxiety and panic disorders. (Teleranta 2003) Paivi Pohjavaara, a researcher at the University of Oulu, Finland, did a statistical analysis on 169 Telaranta patients who had undergone ETS surgery to treat psychiatric conditions from 1995-2000. Patients were given subjective questionnaires before, and then at various points in time after surgery (1 month, 6 months, 1 year, and annually after that). The questions were designed to quantify the patients' subjective experience of concepts such as "alertness", and "fear of observation". The changes produced by sympathectomy were derived by simply subtracting the "after" numbers from the "before" numbers. center| Changes in Psychic Symptoms after ETS Changes in the psychic symptoms of social phobia presented as remainders of equation: (preoperative symptom severity) minus (postoperative symptom severity). The simple table conveys what has happened. These patients are less alert, less embarrassed, experience less fear, and less anxiety than they did before ETS. (see Pohjavaara 2004) Los Angeles surgeon Farshad Malekmehr also offers ETS surgery for social phobia and anxiety. (Malekmehr website) His website presents a diagram which is instructive. center| Cycle of Social Phobia Whether intended or not, Malekmehr's diagram makes for a simple schematic representation of the concepts empirically explored by Critchley and the British team. "COGNITIVE SYMPTOMS" would occur in the brain, and "PHYSICAL SIGNS" would occur in the effectors. ETS would indeed "break the cycle", interrupting not only the brain signals to effectors, but also the (now diminished or non-existent) feedback information from effectors back to the brain. In December 2006, Bracha et al. have published a paper whose title makes a very insightful analogy: "A surgical treatment for anxiety-triggered palmar hyperhidrosis is not unlike treating tearfulness in major depression by severing the nerves to the lacrimal glands." Bracha's analogy is harshly critical of ETS, to be sure, but does not go far enough. It would be a better analogy if severing the nerves to the lacrimal glands also affected a dozen other body systems. Still, the authors sound alarm bells: "Referring an anxious patient with palmar hyperhidrosis to surgery without first completing a proper trial of psychotropic medication may constitute malpractice especially if the patient experiences some of the more severe surgical complications which can occur during sympathectomy" (Bracha et al. 2006 emphasis added)